Antibiotics crisis: is phage therapy the answer?

Bacteriophage – or ‘phage’ for short – is a virus that infects bacteria. These naturally occurring infective agents contaminate bacterium and replicate once within. They are everywhere – including all over our bodies where they outnumber bacteria 10 to one – and are one of the most common entities in the biosphere.

Phages "till" about half the bacteria on the planet every two days. "They are extremely lethal to bacteria," explains Nick Conley, co-founder and chief executive of EpiBiome, a company working to provide antibiotics-free therapies to fight infectious diseases in both humans and agriculture. "They are found at their densest in the ocean."

Why are we talking about this obscure little virus category? Well living as we do in an age where overreliance on antibiotics has resulted in their growing impotence as a treatment for infection – not to mention the creation of superbugs – it is less than comforting to discover phage therapy has been a viable alternative for nearly 100 years.

In 1917, studying the stool samples of dysentery sufferers, French-Canadian microbiologist Felix d’Herelle found bacteriophages always appeared in his patients shortly before recovery. He put two and two together. Since then, phage therapy has proven effective in treating pathogenic bacterial infections. It has been used in dentistry, veterinary science and agriculture as well as human medicine. The therapy spread worldwide during the years between the first and second world wars. “However, once penicillin was discovered in 1928, many people focused their attention on antibiotics,” explains Conley.

Kill ’em all

“Of course, back then all bacteria were considered bad and penicillin was known to kill everything. So antibiotics became the solution and phage-based treatments were no longer pursued.”

The discovery of antibiotics provided the opportunity to treat a wide range of potentially life-threatening infections. Phage therapy was also being developed as a concept. However, the sophisticated research tools necessary to advance phage therapy were only developed relatively recently in the West.

To this day, however, the humble bacteriophage has been in regular use behind the former Iron Curtain by medics in countries such as Russia, Georgia and Poland.

How do they work?

Finding a phage for a bacterial target is pretty straightforward. Not only is there an almost inexhaustible supply all around us, two identical phages have yet to be discovered. So as a bacterium becomes resilient to one phage, medics can just add more types to any viral mix being administered. Stocks of phage varieties are updated every few months but researchers don’t even need to know what specific combination of phages have worked in each bacterial infection. Proponents believe phage therapy should be viewed in the same way the seasonal influenza vaccine is: a treatment that must be updated each year as new flu/bacterial strains present themselves.

EpiBiome

San-Francisco-based start-up EpiBiome is attempting to reintroduce phage therapy back to the West through collaboration with experts at the Hirszfeld Institute in Warsaw, Poland. Focusing its efforts on bovine agriculture, the company is looking at alternatives to shared-class antibiotics: those used to treat infections in both animals and humans.

There are other start-ups doing various phage therapy-based work but raising venture capital hasn’t been easy because it is such an old technology. Venture capitalists want to know what’s changed in the last 100 years that might make phage therapy successful now.

Its success in treating infections where antibiotics have failed has not been in any doubt for Andrzej Gorski of the Hirszfeld Institute, who has been using phage therapy for decades.

"Georgia is the country where phage therapy has traditionally been used most in eastern Europe, " he says. "But historically it is believed the therapy was first initiated during the October Revolution."

The therapy’s survival in eastern Europe and not elsewhere is in part because of the absence of a formal body of public research outlining its potential uses and shortcomings. In other words, its effectiveness hasn’t been validated at the levels we’ve come to demand in the West. “Regulations were not so strict here until recently,” says Dr Gorski. “After all, the CEECs only joined the EU 11 years ago and were until then not subject to the same level of medical scrutiny.”

Phage therapy’s glasnost

A number of clinical trials are being run in the West but most are far from completion. For example, a French start-up is currently performing a clinical trial funded by the European Commission involving phages for bacterial infections in burn patients. The results will be published next year. "We may not have the exact type of evidence required by western medical standards to prove the efficacy of phage therapy but we still have good reason to believe that it can bring about the eradication of bacterial infections and the overall improvement of the clinical status of many patients," says Dr Gorski.

Shortcomings

This is by no means the wonder drug that will solve the challenges now faced by medics using antibiotics. "On a personalised medicinal basis, it's easy to administer but it's difficult on a commodity scale, which doesn't correspond with the western large-scale approach to manufacturing medicine," explains Dr Aaron Hammack, co-founder and director of EpiBiome, which has just been accepted into Stanford's StartX Accelerator Programme.

Not only that, but phage therapy has never been demonstrated unequivocally to be safe. "Because bacteriophages interact with each other all the time in nature and form hybrids, there is an onus on researchers to investigate potential adverse consequences of using phages for therapy," says David C Coleman, professor and chair of oral and applied microbiology at Trinity College Dublin. "Will phage therapy result in the generation of hybrid phages that can transfer toxin or virulence genes to harmless bacterial strains enabling them to cause disease? Will phage therapy result in the selection of bacteria that are resistant to killing by phages? The latter is very likely in my view, as many bacteriophages already carry genes that can confer phage resistance on their bacterial hosts. Much more research is needed in this area."

Commercially, things have been looking up for EpiBiome of late as Silicon Valley Bank (svb.com) agreed to a $1 million debt financing for the start-up. “It is the only debt financing we’ve taken to date,” says Conley. “It’s definitely a good sign when a bank gives a start up a $1 million loan.”

While the company is keen to make a buck out of this venture, any start-up entering the medical sphere knows success is subject to numerous variables. Not only does it take up to 15 years to bring any new medication for human patients to market, the costs associated with clinical trials, FDA approval etc can often end up costing upwards of $1 billion.

In the animal pharmaceuticals market, however, the costs are far lower – some $15 million – to commercialise a new drug. “We’re still regulated by the FDA through the Centre for Veterinary Medicine and many of the pathogens were targeting in animals – E coli, Strep etc – are the same ones that affect humans,” says Conley.

The bigger picture

Phage therapy might indeed become one alternative to antibiotics for the treatment of bacterial infections. But given what hindsight has taught us about the misuse of antibiotics – plus the fact that not all bacteria are bad bacteria – how do we avoid making similar mistakes with phage therapy were it to become a widely available treatment?

“Phage therapy involves the simultaneous use of mixtures of different phages to ensure efficient killing of the target bacterial species,” says Coleman. “Overuse or inappropriately targeted phage therapy could result in the destruction of beneficial or “good bacteria”. Our bodies and mucous membranes are covered in “good” bacteria that exclude disease-causing bacteria. Killing off these friendly bacteria by inappropriately targeted phage therapy could result in subsequent infection by bacterial pathogens.

“In my view, a lot of research needs to be undertaken on potential downstream and long-term adverse effects of phage therapy for human and animal infections.

“Bacteriophages have coexisted with bacteria for millions of years. They frequently co-operate with each other for their mutual benefit. In addition, we know now that bacteria are masters of adaptation and rapid evolution. Bacteria have developed or acquired resistance to most antibiotics within a few years of their release into clinical use. I have no doubt that the widespread use of phage therapy will drive the emergence of phage resistant bacteria in the same way.”

Despite the scepticism, the momentum is growing behind researchers – and investors – trying to push this therapy back into the mainstream. For Conley at EpiBiome, the crisis posed by antibiotic immunity places a moral imperative on everyone in the medical profession to look for alternatives, regardless of the concerns raised.

“When people think about antibiotic-resistant bacteria, they often worry about dying of an infection from one of these superbugs,” he says. “While that would be an agonising death, that’s only a very small piece of the total human impact. The far scarier point that is not being highlighted is the very real threat posed by losing access to the last 100 years of surgical advances. Because the risk of post-operative infection may become too high to perform most procedures, antibiotic resistance will completely change the risk:benefit ratio of a surgical procedure.

“Imagine a world where you can no longer get Lasik, wisdom teeth removed, a tonsillectomy, a vasectomy etc? This is a dramatically different world to the one we live in today, and one that awaits us if we continue on our current path.”